A main objective of theoretical computational chemistry is to provide meaningful quantitative insight into practical chemical applications. However, the compute-intensive nature of most theoretical calculations precludes application to large macromolecular systems. Extension of theory into the realm of macromolecular phenomena requires computational methods that are efficient and that have well-behaved scaling properties. We propose to develop and apply improved biomolecular force fields to study biological macromolecules in solution. In particular, we intend to extend conventional models to take into account many-body effects using the recently developed chemical potential equalization (CPE) method based on density-functional theory. Applications of the method will focus on highly ionic systems where many-body effects are dominant such as DNA and modified DNA analogs, and DNA binding proteins. We further propose to develop hybrid QM/MM methods to study chemical reactions of macromolecules in solution such as the HIV-1 reverse transcriptase enzyme. Hybrid force fields will be derived rigorously using the electron density as the basic variable by combining the CPE method with new linearly scaling density-functional methods. We anticipate the proposed theoretical methods will overcome many of the difficulties inherent in conventional models, and be of general utility to the field of molecular modeling.